Efficacy, Safety, and Tolerability of Beclometasone Dipropionate, Formoterol Fumarate, and Glycopyrronium Bromide in COPD: A Randomized, Double-Blind Study

The primary objective of this study is to demonstrate the efficacy of **CHF 5993** in improving pre-dose lung function, specifically the pre-dose morning Forced Expiratory Volume in 1 second (**FEV1**), compared with **CHF 1535** in subjects with Chronic Obstructive Pulmonary Disease (**COPD**). This is clinically relevant as it aims to enhance baseline respiratory function, which is crucial for managing COPD symptoms and improving patient outcomes.

Secondary objectives include:

• Demonstrating the efficacy of CHF 5993 to improve post-dose lung function (2-hour post-dose FEV1) compared with CHF 1535.
• Demonstrating the efficacy of CHF 5993 to reduce the annual rate of moderate and severe COPD exacerbations compared with CHF 1535.
• Demonstrating the efficacy of CHF 5993 to improve health-related quality of life, indicated by a decrease from baseline in total St. George's Respiratory Questionnaire (**SGRQ**) score by ≥4, compared with CHF 1535.
• Assessing the long-term safety and tolerability of CHF 5993 compared with CHF 1535.
• Evaluating the effect of CHF 5993 on other lung function parameters, the subject's health status, and clinical outcome measures compared with CHF 1535.

The clinical trial involves a total of **1467 participants** diagnosed with **chronic obstructive pulmonary disease (COPD)**. The study population includes both male and female subjects aged over 40 years, who are either current or ex-smokers with a history of at least 10 pack-years, having quit smoking at least 6 months prior to screening. Participants are required to have a documented COPD diagnosis for at least 12 months before the screening visit, in accordance with the GOLD 2020 Report. The trial population was selected based on their stable use of daily inhaled maintenance therapy for COPD, with a stable dose for at least 3 months prior to screening and randomization. Participants must demonstrate a cooperative attitude and the ability to correctly use pMDI inhalers and eDiary. The study includes an outpatient population, with symptomatic subjects having a COPD Assessment Test (CAT) score of 10 or higher. Key lifestyle considerations include a history of smoking and the requirement for a stable medication regimen. The trial does not specifically exclude vulnerable populations, as indicated by the inclusion of such groups in the study design.

The clinical trial is a **randomized**, **double-blind**, 52-week, two-arm parallel group study designed to evaluate the efficacy, safety, and tolerability of a fixed-dose triple combination of **beclometasone dipropionate**, **formoterol fumarate**, and **glycopyrronium bromide** (CHF 5993) compared to a fixed-dose dual combination of beclometasone dipropionate and formoterol fumarate (CHF 1535). Both treatments are administered via a pressurized metered-dose inhaler (pMDI) to subjects with **chronic obstructive pulmonary disease (COPD)**. The primary objective is to demonstrate the efficacy of CHF 5993 in improving pre-dose lung function, specifically pre-dose morning FEV1, compared to CHF 1535. The trial will also assess secondary endpoints, including changes in 2-hour post-dose morning FEV1, the rate of moderate and severe COPD exacerbations, and the incidence of treatment-emergent adverse events.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria such as a documented COPD diagnosis, stable inhaled maintenance therapy, and a history of smoking. Participants will be randomly assigned to one of the two treatment groups. The study will include multiple follow-up visits, with a key assessment at week 28 to evaluate the primary endpoint. The end-of-study visit will occur at week 52, marking the completion of the trial. Participants are expected to be involved for the entire 52-week duration unless early termination is warranted due to adverse events, non-compliance, or withdrawal of consent.

Inclusion criteria require participants to be male or female subjects over 40 years of age, with a history of COPD for at least 12 months, and a smoking history of at least 10 pack-years. Exclusion criteria are not specified in the provided data. The trial is not categorized as low intervention and is conducted under phase III conditions. The estimated recruitment start date was April 27, 2022, with an anticipated end date of August 11, 2025. The trial is conducted in accordance with ethical standards, requiring signed informed consent from all participants prior to any study-related procedures.

The clinical trial involves the administration of two experimental medications, both delivered as **pressurised inhalation solutions**. The first medication, CHF1535 pMDI 100/6, is a fixed-dose dual combination containing **formoterol fumarate dihydrate** and **beclometasone dipropionate anhydrous**. This medication is administered via **inhalation use**. The maximum daily dose is 424 micrograms, with a total maximum dose of 154.34 milligrams over the treatment period. The treatment duration is set for 52 weeks. CHF1535 pMDI 100/6 is classified under the category of ICS/LABA (Inhaled Corticosteroid/Long-Acting Beta-Agonist) and is not a paediatric formulation.

The second experimental medication, CHF5993 pMDI-US, is a fixed-dose triple combination comprising **glycopyrronium bromide**, **formoterol fumarate dihydrate**, and **beclometasone dipropionate anhydrous**. This medication is also administered via **inhalation use**. The maximum daily dose for CHF5993 pMDI-US is 474 micrograms, with a total maximum dose of 172.54 milligrams over the treatment period. The treatment duration is similarly set for 52 weeks. CHF5993 pMDI-US falls under the category of ISC/LABA/Antimuscarinic agent and is not a paediatric formulation.

In addition to the experimental medications, a **training kit** is utilized in the study. The training kit does not contain any active substances and is not associated with any specific pharmaceutical form or route of administration. It serves as a non-experimental component to aid in the proper use of the inhalation devices by participants. The training kit is not intended for therapeutic use and does not contribute to the treatment regimen.

The efficacy of the investigational product in this clinical trial will be assessed primarily through the change from baseline in pre-dose morning **FEV1** (Forced Expiratory Volume in one second) at week 28. This parameter serves as the primary endpoint to evaluate the improvement in lung function in subjects with Chronic Obstructive Pulmonary Disease (COPD). Secondary endpoints include the change from baseline in 2-hour post-dose morning FEV1 at week 28, the rate of moderate and severe COPD exacerbations over the 52-week treatment period, and the St. George's Respiratory Questionnaire (SGRQ) response, defined as a decrease from baseline in total score of at least 4 at week 28.

Additional secondary endpoints involve the incidence of treatment-emergent adverse events (TEAEs), adverse drug reactions (ADRs), serious ADRs, serious adverse events (SAEs), severe AEs, TEAEs leading to discontinuation from the study drug, and TEAEs leading to death. The incidence of treatment-emergent pneumonia and major adverse cardiovascular events (MACE) will also be monitored. These efficacy parameters will be measured and collected at specified timepoints throughout the study, with the primary focus on week 28 for the primary endpoint and over the entire 52-week period for secondary endpoints. The assessments will be conducted using validated scales and laboratory tests to ensure accuracy and reliability of the data collected.